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WO2009110519A1 - Nouveau dérivé de 1-aminocarbonyl-pipéridine - Google Patents

Nouveau dérivé de 1-aminocarbonyl-pipéridine Download PDF

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Publication number
WO2009110519A1
WO2009110519A1 PCT/JP2009/054093 JP2009054093W WO2009110519A1 WO 2009110519 A1 WO2009110519 A1 WO 2009110519A1 JP 2009054093 W JP2009054093 W JP 2009054093W WO 2009110519 A1 WO2009110519 A1 WO 2009110519A1
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group
alkyl
groups
alkoxy
amino
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PCT/JP2009/054093
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English (en)
Japanese (ja)
Inventor
道律 小澤
智也 城
慶介 柿口
眞里 伊藤
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大日本住友製薬株式会社
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Publication of WO2009110519A1 publication Critical patent/WO2009110519A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a novel 1-aminocarbonylpiperidine derivative having an excellent antiallergic action, a physiologically acceptable salt thereof, and a pharmaceutical composition containing them.
  • allergic diseases such as bronchial asthma, allergic rhinitis, urticaria, atopic dermatitis and contact dermatitis have increased due to air pollution and changes in house structure (sealing, heating and cooling, etc.) .
  • steroids are mainly used to treat these allergic diseases, but steroids often cause serious side effects.
  • several drugs that have immunosuppressive effects are also said to be effective in the prevention and treatment of allergic diseases, but their use is also restricted because of serious side effects.
  • existing antihistamines and anti-inflammatory agents are also used for the treatment of allergic diseases as symptomatic treatments, but these drugs do not show a sufficient therapeutic effect particularly in atopic dermatitis. Therefore, a new non-steroidal antiallergic agent effective by oral administration for the prevention and treatment of allergic diseases is eagerly desired.
  • Patent Document 1 discloses a protein inhibitor represented by the following general formula. It is described that the compound is used for the treatment of osteoporosis, periodontal disease, osteoarthritis and the like.
  • the nitrogen atom of the piperidine ring of the compound of the present invention is substituted with —C ( ⁇ O) —NH—R 1 , and the corresponding substituent R 5 of the following compound has such a substituent. Not. Therefore, the chemical structure is clearly different from the compound of the present invention.
  • R 1 is R ′′, R ′′ C (O), R ′′ C (S), R ′′ SO 2 , R ′′ OC (O), R ′′ R′NC (O), or R ′.
  • R 2 is H, C 1-6 alkyl, C 2-6 alkenyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl
  • R 3 is H, C 2-6 alkenyl, C 2-6 alkynyl, Het, Ar, etc .
  • R 4 is Ar—C 0-6 alkyl, Het-C 0-6 alkyl, etc .
  • R 5 represents R 6 —N (R 1 ) —C (R 7 ) —Z—, Ar—C 0-6 alkyl, Het—C 0-6 alkyl, adamantyl-C (O) —, Ar—C (O )-, Or Het-C (O)-
  • Each R ′ is independently H, C 1-6 alkyl, C 2-6 alkenyl, Ar—C 0-6 alkyl, or Het-C 0-6 alkyl
  • Each R '' are independently C 1-6 alkyl, C 3-6 cycloal
  • Patent Document 2 discloses a PGD2 receptor antagonist represented by the following general formula.
  • the compound is described to be used for the treatment of inflammatory diseases (allergic rhinitis, allergic asthma, atopic dermatitis, chronic obstructive pulmonary disease, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease or skin disorder) Yes.
  • the compound has a piperidine ring, but this piperidine ring is a condensed bicyclic heterocyclic ring that is always condensed with another monocyclic aromatic ring, and the chemical structure is clearly different from the compound of the present invention. .
  • ring A is an optionally substituted monocyclic aromatic ring;
  • R is —X 1 —R 1 ;
  • R x is —X 2 —R 4 ;
  • R 3 is an optionally substituted cycloaliphatic group, aromatic group or the like;
  • X is —C (R 2 ) 2 — and the like;
  • X 1 and X 2 are each independently a bond, C (O), C (O) NH, etc .;
  • R 1 is H or an optionally substituted cycloaliphatic group, aromatic group or non-aromatic heterocyclic group;
  • R 2 is independently H, —X 4 —R 8 and the like;
  • R 4 is H, —X 6 —R 10 or the like;
  • X 4 and X 6 are each independently a linear or branched hydrocarbyl group, wherein the hydrocarbyl group is optionally selected from one or more selected from the group consisting of halo, —OH, ⁇ O, and
  • R 5 and R 6 are each independently H or C 1 -C 3 alkyl; and R 8 and R 10 are each independently H, a cycloaliphatic group, an aromatic group, a non-aromatic heterocyclic group, or the like; ]
  • Patent Document 3 discloses a PGD2 receptor antagonist represented by the following general formula.
  • the compounds are described for use in the treatment of inflammatory diseases (allergic rhinitis, rheumatoid arthritis, chronic obstructive pulmonary disease, atopic dermatitis or allergic asthma).
  • the compound has a piperidine ring, but this piperidine ring is a condensed bicyclic heterocyclic ring that is always condensed with another monocyclic aromatic ring, and the chemical structure is clearly different from the compound of the present invention. .
  • ring A is an optionally substituted monocyclic aromatic ring;
  • R is —X 1 —R 1 ;
  • R x is —X 2 —R 4 ;
  • X 1 and X 2 are each independently C (O), C (O) NH, etc .;
  • R 1 is a substituted 5- to 6-membered aromatic ring group or heteroaromatic ring group;
  • R 2 is a C 1-3 alkyl group;
  • R 3 is an optionally substituted monocyclic or bicyclic group selected from an aromatic ring, a heteroaromatic ring, a non-aromatic carbocycle, or a non-aromatic heterocycle;
  • R 4 is an optionally substituted C 1-6 alkyl group or the like;
  • Patent Document 4 discloses a serotonin and noradrenaline reuptake inhibitor represented by the following general formula.
  • the compound may be used in the treatment of diseases involving the inhibition of both serotonin and noradrenaline (urinary incontinence) and diseases that inhibit reuptake of either serotonin or noradrenaline (pain, depression, etc.) Are listed. These uses are completely different from those of the present invention.
  • the examples of this document only disclose compounds in which R 1 is a hydrogen atom, and the group R 3 corresponding to the — (CH 2 ) m — ring A moiety of the compounds of the present invention is het. There is also no specific disclosure of compounds that are 3- C 1-4 alkyl-groups.
  • R 1 is —H, —C (A) Y, —C 3-8 cycloalkyl, —aryl, —het, etc., and these cycloalkyl, aryl or het are selected from B Substituted with at least any one independent substituent, A is S or O; Y is -aryl, -het, etc. B is —C 1-8 alkyl, —C 1-8 alkoxy, —OH, —halo, —CF 3 , —OCF 3 , C 1-4 alkoxy-C 1-6 alkyl-, etc.
  • R 2 is aryl 1 or het 1 , each optionally substituted with at least one independent substituent selected from D;
  • Aryl 1 is independently selected from phenyl, naphthyl, etc.
  • het 1 is a 5- to 10-membered aromatic heterocycle containing at least one N, O or S heteroatom, optionally containing an aryl group,
  • D represents —C 1-8 alkyl, —C 1-8 alkoxy, —OH, —halo, —CF 3 , —OCF 3 , C 1-4 alkoxy-C 1-6 alkyl-, —C 3-8 cyclo Alkyl, etc.
  • R 3 is -het 3 , het 3 -C 1-4 alkyl-, etc., and het 3 etc. is optionally substituted with at least one independent substituent selected from G; het 3 is a 4-, 5- or 6-membered non-aromatic heterocycle containing at least one N, O or S heteroatom, optionally a 5- or 6-membered carbocycle or at least Fused with another 4-, 5- or 6-membered heterocycle containing one N, O or S heteroatom, G is —C 1-8 alkyl, —C 1-6 alkoxy, —OH, —halo, —CF 3, etc., and the alkyl group here may have a substituent, X is a single bond, —C 1-8 alkyl or the like, When n is 1, m is 0 or 1 or the like. ]
  • Non-Patent Document 1 discloses compounds represented by the following general formula, and describes that these compounds are useful as analgesics and local anesthetics.
  • X is N (CH 3 )
  • the compound is a compound having a piperidine ring, but since the only substituent of the nitrogen atom of the piperidine ring is only a methyl group, it is clearly the compound of the present invention.
  • the chemical structure is different.
  • R 1 is a methyl group
  • R 2 and R 3 are a hydrogen atom or a methyl group
  • NR 4 R 5 is N (CH 2 ) 2 , N (CH 2 CH 3 ) 2 , pyrrolidinyl group, piperidinyl group or morpholinyl group
  • X is an oxygen atom, a sulfur atom or N (CH 3 ).
  • the present inventors have found a novel compound having a non-steroidal chemical structure and exhibiting an excellent antiallergic action, and completed the present invention.
  • a novel 1-aminocarbonylpiperidine derivative represented by the following general formula (I) or a physiologically acceptable salt thereof hereinafter sometimes referred to as “the compound of the present invention”
  • a pharmaceutical composition containing the compound is provided.
  • ring A is azetidin-1-yl group, pyrrolidin-1-yl group, piperidino group, piperazin-1-yl group, morpholino group, hexahydroazepin-1-yl group, hexahydrodiazepine- 1-yl group, aziridin-1-yl group, perhydroisoquinolin-2-yl group, perhydroquinolin-1-yl group, 1,2,3,4-tetrahydroisoquinolin-2-yl group, 1,2, 3,4-tetrahydroquinolin-1-yl group, 2,3-dihydroindol-1-yl group, perhydroindol-1-yl group, 1,3-dihydroisoindol-2-yl group, perhydroisoindole -2-yl group, pyrazolidin-1-yl group, tetrahydroimidazol-1-yl group, hexahydr
  • phenyl groups are a halogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C 1-3 alkoxy-C 1- 3 alkyl groups, C 1-3 alkoxy-carbonyl groups, C 1-3 alkyl-carbonyl groups, C 1-3 alkylthio groups, C 1-3 alkyls
  • a C 3-8 cycloalkyl group the C 3-8 cycloalkyl group
  • Optionally substituted with a kill group) and an amino group (the amino group may be substituted with one or two identical or different C 1-3 alkyl groups, or a C 1-3 alkyl-carbonyl group).
  • the optionally substituted C 3-8 cycloalkyl group for R 1 is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, an amino group.
  • a group (the amino group may be substituted by one or two identical or different C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups) and a phenyl group [the phenyl group is a halogen atom; , Hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C 1-3 alkoxy-C 1-3 alkyl group, C 1- 3 alkoxy - carbonyl group, C 1-3 alkyl - carbonyl group, a trifluoromethyl group, C 1-3 alkylthio group, C 1-3 A Alkylsulfonyl group and an amino group (said amino group may contain one or two identical or different C 1-3 alkyl optionally substituted with a group) with 1 to 4 atoms or groups selected from the group consisting of Means an optionally substituted C 3-8 cycloalkyl group substituted with 1 to 4 atom
  • a carboxyl group, a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, C 1 -3 alkoxy-C 1-3 alkyl group, C 1-3 alkoxy-carbonyl group, C 1-3 alkyl-carbonyl group, trifluoromethylcarbonyl group, C 1-3 alkylthio group, C 1-3 alkylsulfonyl group and amino group (said amino group may be substituted by one or two identical or different C 1-3 alkyl group It may be substituted with 1 to 4 atoms or groups selected from the group consisting of], C 3-8 cycloalkyl group, C 1-3 alkoxy -C 1-3 alkyl group, C 1-6 alkoxy - A carbonyl group, a C 1-6
  • R 2 represents a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, or a carboxyl group.
  • C 1-3 alkoxy-C 1-3 alkyl group C 1-3 alkoxy-carbonyl group, C 1-3 alkyl-carbonyl group, trifluoromethylcarbonyl group, C 1-3 alkylthio group, C 1-3 alkyl 1 selected from the group consisting of a sulfonyl group and an amino group (the amino group may be substituted with one or two identical or different C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups) Optionally substituted with up to 5 atoms or groups] or a C 3-8 cycloalkyl group wherein the C 3-8 cycloalkyl group is a halogen An atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or two C 1-3, which are the same or different) And optionally substituted with 1 to 4 atoms or groups selected
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, or a C 1-6 alkyl.
  • a phenyl group [the amino group is one or the same or different two C 1-6 alkyl groups, C 1-3 alkyl-carbonyl group or aminocarbonyl group (the aminocarbonyl groups are the same or different May be substituted with two C 1-6 alkyl groups)]
  • a phenyl group [the phenyl group is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1- 6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group and an amino group (said amino group may contain one or two identical or different C 1-3 Alkyl optionally substituted with 1 to 5 atoms or groups selected from the group consisting of a may be) optionally substituted with a group], a benzyl group [said benzyl group, a halogen atom, hydroxy group, C 1- A 6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group,
  • ring A is an azetidin-1-yl group, pyrrolidin-1-yl group, piperidino group, morpholino group, piperazin-1-yl group or hexahydroazepin-1-yl group Or a physiologically acceptable salt thereof.
  • R 1 is a halogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, carboxyl group, phenyl group
  • phenyl Group includes a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or two of the same or different Optionally substituted with 1 to 4 atoms or groups selected from the group consisting of a C 1-3 alkyl group), a C 3-8 cycloalkyl group, a C 1-6 alkoxy - carbonyl group, C 1-6 alkyl - carbonyl group, a trifluoromethyl group, C 1-3 alkylthio group, C 1-3 alkylsulfonyl group Amino group and (said
  • R 1 is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one or the same or A phenyl group optionally substituted with 1 to 5 atoms or groups selected from the group consisting of two optionally substituted C 1-3 alkyl groups or C 1-3 alkyl-carbonyl groups) Or a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and an amino group (the amino group is one, or two identical or different C 1-4 atom or cyclohexyl group der optionally substituted with a group selected from 1-3 group consisting of alkyl optionally substituted with a group) Compound or a physiologically acceptable salt thereof according to any one of the above (1) to
  • R 2 is a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, or an amino group (the amino group is Substituted with 1 to 5 atoms or groups selected from the group consisting of one or two identical or different C 1-3 alkyl groups or optionally substituted with C 1-3 alkyl-carbonyl groups)
  • the compound or a physiologically acceptable salt thereof according to any one of the above (1) to (4), which is an optionally substituted phenyl group; or a C 3-8 cycloalkyl group.
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkyl-carbonyl group, trifluoromethyl A group, an aminocarbonyl group (the aminocarbonyl group may be substituted with two identical or different C 1-6 alkyl groups) and an amino group (the amino group is one or two identical or different The compound according to any one of (1) to (5) above, which may be substituted with a C 1-3 alkyl group or a C 1-3 alkyl-carbonyl group, or a physiologically acceptable product thereof salt.
  • Ring A is a pyrrolidin-1-yl group, piperidino group, morpholino group or piperazin-1-yl group
  • R 1 is a phenyl group which may be substituted with 1 to 5 atoms or groups selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group and a trifluoromethyl group.
  • R 2 is a phenyl group;
  • R 3 and R 4 are the same or different and are a hydrogen atom or a C 1-6 alkyl group,
  • a pharmaceutical composition comprising the compound according to any one of (1) to (9) above or a physiologically acceptable salt thereof as an active ingredient.
  • antiallergic agents include allergic dermatitis, allergic rhinitis, bronchial asthma, atopic dermatitis, contact dermatitis It can be used for the prevention and / or treatment of allergic diseases such as urticaria, eczema, allergic ophthalmitis, hay fever, and other inflammatory diseases.
  • the physiologically acceptable salt of the compound represented by the formula (I) means a physiologically acceptable acid addition salt.
  • inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and oxalate, maleate, fumarate, malonate, lactic acid Organic salts such as salts, malates, citrates, tartrate, benzoates, methanesulfonates, p-toluenesulfonates, gluconates and the like.
  • the compounds of the present invention may be crystalline or amorphous and may exist in the form of hydrates and / or solvates, these hydrates and / or solvates Are also encompassed by the compounds of the present invention.
  • Compounds containing various amounts of water obtained by methods such as stoichiometric amounts of hydrates and lyophilization are also within the scope of the present invention.
  • C 1-6 ”, “C 3-8 ” or “C 1-3 ” means that the carbon number of the substituent described immediately thereafter is 1 to 6, 3 to 8, or 1 to 3 means.
  • C 1 alkyl-carbonyl means an acetyl group.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include, for example, methyl group, ethyl group, propyl group, isopropyl group Group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group and the like. Of these, a methyl group and the like are preferable.
  • Specific examples of the “C 1-3 alkyl group” include a substituent having 1 to 3 carbon atoms in the above examples.
  • the “C 1-6 alkoxy group” may be linear or branched, and specific examples thereof include, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec -Butoxy group, tert-butoxy group and the like. Of these, a methoxy group and the like are preferable.
  • Specific examples of the “C 1-3 alkoxy group” include a substituent having 1 to 3 carbon atoms in the above examples.
  • C 1-3 alkoxy-C 1-3 alkyl group may be either linear or branched, and specific examples thereof include, for example, methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxy group Examples thereof include a methyl group, a methoxyethyl group, an ethoxyethyl group, a propoxypropyl group, and an isopropoxypropyl group.
  • the “C 1-6 alkoxy-carbonyl group” may be either linear or branched, and specific examples thereof include, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxy A carbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group and the like can be mentioned.
  • Specific examples of “C 1-3 alkoxy-carbonyl group” include a substituent having 1 to 3 carbon atoms in the alkoxy moiety in the above examples.
  • the “C 1-6 alkyl-carbonyl group” may be either linear or branched, and specific examples thereof include, for example, acetyl group, ethylcarbonyl group, propylcarbonyl group, isopropylcarbonyl group, butylcarbonyl group , Isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group and the like.
  • Specific examples of the “C 1-3 alkyl-carbonyl group” include a substituent having 1 to 3 carbon atoms in the alkyl moiety in the above examples.
  • C 1-3 alkylthio group may be either linear or branched, and specific examples thereof include a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.
  • the “C 1-3 alkylsulfonyl group” may be linear or branched, and specific examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group.
  • C 3-8 cycloalkyl group means a monovalent group of a cycloalkane having 3 to 8 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
  • the “C 1-6 alkyloxadiazolyl group” may have either a linear or branched C 1-6 alkyl moiety. Specific examples thereof include, for example, methyloxadiazolyl group, ethyloxadiazolyl group Group, propyloxadiazolyl group, isopropyloxadiazolyl group, butyloxadiazolyl group, isobutyloxadiazolyl group, sec-butyloxadiazolyl group, tert-butyloxadiazolyl group, pentyloxadiazolyl group, isopentyl An oxadiazolyl group, a hexyl oxadiazolyl group, etc. are mentioned.
  • the “optionally substituted C 3-8 cycloalkyl group” means a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group at each substitutable position.
  • the phenyl group is a halogen atom, hydroxy group, C 1-6 alkyl group, C 1-6 alkoxy group, trifluoromethyl group, trifluoromethoxy group, cyano group, nitro group, C 1-3 alkoxy-C 1- 3 alkyl group, C 1-3 alkoxy - carbonyl group, C 1-3 alkyl - carbonyl group, a trifluoromethyl group, C 1-3 alkyl O group, C 1-3 alkylsulfonylamino group and an amino group (said amino group may contain one or two identical or different C 1-3 alkyl optionally substituted by a group) 1 selected from the group consisting of Means a C 3-8 cycloalkyl group optionally substituted with 1 to 4
  • C 3-8 cycloalkyl group which may be substituted include, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, 4-methylcyclohexyl group, 4-tert- Butylcyclohexyl group, 4,4-dimethylcyclohexyl group, 3,3,5,5-tetramethylcyclohexyl group, 4-fluorocyclohexyl group, 4-hydroxycyclohexyl group, 4-trifluoromethylcyclohexyl group, 4-methoxycyclohexyl group 4-phenylcyclohexyl group, 4- (4-chlorophenyl) cyclohexyl group, and the like.
  • the “optionally substituted phenyl group” is a halogen atom, a hydroxy group, or a C 1-6 alkyl group at each substitutable position (the C 1-6 alkyl group is each at a substitutable position).
  • the optionally substituted phenyl group include, for example, a phenyl group, a 3-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 2-methylphenyl group, 4- (1,1,1, 1,3,3,3-hexafluoro-2-hydroxypropyl) phenyl group, 2-methoxyphenyl group, 4-trifluoromethylphenyl group, 4-trifluoromethoxyphenyl group, 4-cyanophenyl group, 4-chloro -3-nitrophenyl group, 4-phenylphenyl group, 4- (4-chlorophenyl) phenyl group, 4-cyclohexylphenyl group, 3-carboxylphenyl group, 4-methoxycarbonylphenyl group, 2-acetylphenyl group, 4- (2,2,2-trifluoroacetyl) phenyl group, 4-methylthiophenyl group, 4-methyls Ph
  • 4-trifluoromethylphenyl group 4-fluorophenyl group, 2-trifluoromethylphenyl group, 4-isopropylphenyl group, 4-methoxyphenyl group, 3-trifluoromethylphenyl group and the like are preferable.
  • Heterocyclic group '' means a pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, benzoimidazolyl group, indolyl group, isoindolyl group, azaindolyl group, indazolyl group, indolinyl group, isoindolinyl group, quinolyl group, An isoquinolyl group, a quinazolinyl group, a cinnolinyl group, a furyl group, a pyranyl group, a benzofuranyl group, a chromenyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group, or a benzoisoxazolyl group.
  • Heterocyclic group means a halogen atom, a hydroxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group at each substitutable position.
  • Carboxyl group, Le group [the phenyl group, a halogen atom, hydroxy group, C 1-6 alkyl, C 1-6 alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a nitro group, C 1-3 alkoxy - A C 1-3 alkyl group, a C 1-3 alkoxy-carbonyl group, a C 1-3 alkyl-carbonyl group, a trifluoromethylcarbonyl group, a C 1-3 alkylthio group, a C 1-3 alkylsulfonyl group, and an amino group
  • the amino group may be substituted with 1 to 4 atoms or groups selected from the group consisting of 1 or 2 identical or different C 1-3 alkyl groups), C 3-8 cycloalkyl group, C 1-3 alkoxy -C 1-3 alkyl group, C 1-6 alkoxy - carbonyl group, C 1-6 alkyl - carbonyl
  • a heterocyclic group which may be substituted with 1 to 4 atoms or groups Preferable specific examples of the heterocyclic group which may be substituted with these substituents at each substitutable position include, for example, each of the above heterocyclic groups, 3-phenylfuryl group, 2-trifluoromethylpyridyl.
  • Halogen atom means fluorine, chlorine, bromine or iodine.
  • Ring A is preferably a pyrrolidin-1-yl group, piperidino group, morpholino group, piperazin-1-yl group, etc., more preferably pyrrolidin-1-yl group, morpholino group, piperazine-1 -Yl group and the like.
  • R 1 is preferably an optionally substituted phenyl group, and more preferably selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a trifluoromethyl group. And a phenyl group which may be substituted with 1 to 5 atoms or groups.
  • R 2 is preferably a phenyl group.
  • R 3 and R 4 are preferably a hydrogen atom or a C 1-6 alkyl group.
  • m is preferably 1 or 2.
  • Specific examples of the compound of the present invention include compounds of Examples 1 to 8 described later.
  • Preferred compounds of the present invention include the following compounds or physiologically acceptable salts thereof.
  • the compound of this invention represented by general formula (I) can be manufactured by the manufacturing method shown below.
  • the reaction between the compound of formula (II) and the compound of formula (III) is carried out in the absence of a solvent or in a suitable solvent.
  • the solvent to be used include toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, methylene chloride, chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. These solvents are each alone or in combination of two or more. Used in combination. This reaction is performed in the presence of a base as necessary.
  • the base include an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or triethylamine.
  • organic bases such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine.
  • the reaction temperature is usually ⁇ 40 ° C. to 200 ° C., but preferably ⁇ 20 ° C. to 70 ° C.
  • the compound of the formula (II) can be obtained, for example, by purchasing a commercially available compound or producing it by a known method in which the corresponding carboxylic acid (R 1 —COOH or the like) is used as a raw material to perform the Curtius rearrangement.
  • the compound of the formula (III) can be produced by the method shown in the following scheme.
  • PG means a protecting group
  • R 2 , R 3 , R 4 , m and group: ring A means the same as described in the above (1).
  • Step 1 Compound (2-3) is prepared by reductive alkylation using compound (2-1) and the corresponding primary monoamine (R 2 —NH 2 ) available in a suitable solvent.
  • This reaction is carried out using a reducing agent such as sodium borohydride, sodium triacetoxyborate, sodium cyanoborohydride, picoline-borane, or catalytic reduction using a metal catalyst such as palladium in a hydrogen atmosphere.
  • a reducing agent such as sodium borohydride, sodium triacetoxyborate, sodium cyanoborohydride, picoline-borane, or catalytic reduction using a metal catalyst such as palladium in a hydrogen atmosphere.
  • the solvent to be used include toluene, xylene, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, methanol, ethanol and the like, and these solvents are used alone or in combination of two or more.
  • reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • Compound (2-3) is obtained by reacting the corresponding bromo-substituted aryl or chloro-substituted heteroaryl and compound (2-2) with a palladium catalyst [eg, tris (dibenzylideneacetone) dipalladium], phosphine ligand (eg, 2 ′, 6'-dimethoxy-2-dicyclohexylphosphinobiphenyl) and an organic base (for example, t-butoxy sodium) in the presence.
  • a palladium catalyst eg, tris (dibenzylideneacetone) dipalladium
  • phosphine ligand eg, 2 ′, 6'-dimethoxy-2-dicyclohexylphosphinobiphenyl
  • organic base for example, t-butoxy sodium
  • the solvent to be used examples include toluene, xylene, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, dimethylformamide and the like, and these solvents are used alone or in combination of two or more.
  • the reaction temperature is usually 0 ° C. to 150 ° C., preferably 25 ° C. to 120 ° C.
  • Step 2 Compound (2-4) is produced by reacting compound (2-3) with a corresponding acid halide such as chloroacetic acid chloride, bromoacetic acid bromide, or chloropropionic acid chloride in an appropriate solvent.
  • a corresponding acid halide such as chloroacetic acid chloride, bromoacetic acid bromide, or chloropropionic acid chloride in an appropriate solvent.
  • the solvent to be used include toluene, xylene, tetrahydrofuran, dioxane, chloroform, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. These solvents are used alone or in combination of two or more. Used. This reaction is carried out in the presence of a base as required.
  • the base include inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, Examples thereof include organic bases such as N-methylmorpholine, dimethylaminopyridine, and pyridine.
  • the reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 120 ° C.
  • Step 3 Compound (2-5) is produced by reacting compound (2-4) with the corresponding ring A compound in the absence of a solvent or in a suitable solvent.
  • the solvent to be used include toluene, xylene, tetrahydrofuran, dioxane, methylene chloride, chloroform, acetonitrile, dimethylformamide and the like, and these solvents are used alone or in combination of two or more. This reaction is carried out in the presence of a base as required.
  • the base include inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, Examples thereof include organic bases such as N-methylmorpholine, dimethylaminopyridine, and pyridine. Also, by adding an excess amount of the corresponding ring A compound to the reaction solution, the compound functions as a base.
  • the reaction temperature is usually ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 120 ° C.
  • Compound (III) can be obtained by deprotecting the protecting group of compound (2-5) according to a conventional method.
  • the protecting group include groups that form carbamates such as t-butoxycarbonyl group and benzyloxycarbonyl group, and groups that form benzylamines such as benzyl group and trityl group.
  • the compound of formula (I) obtained by the production method shown above is isolated and purified according to conventional methods such as extraction, silica gel column chromatography, recrystallization, and reprecipitation.
  • extraction solvent diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene or the like is used.
  • Purification by silica gel column chromatography uses acidic, basic, or various chemically treated silica gel or alumina, and developing solvents include, for example, hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, Acetonitrile / water, methanol / water, etc. can be used.
  • each enantiomer can be separated and purified.
  • the optically active compound of formula (I) can also be produced from the reaction of an optically active compound of formula (III) with a compound of formula (II). For example, separation into enantiomers using an optically active acid is performed by forming a diastereomeric salt according to a conventional method, separating the diastereomeric salt, and then converting this into a free base.
  • optically active acid used as the optical resolution agent examples include (+)-or ( ⁇ )-camphoric acid, (1S)-(+)-or (1R)-( ⁇ )-camphor-10-sulfonic acid, L -(+)-Or D-(-)-tartaric acid, (+)-or (-)-mandelic acid, (S)-(-)-or (R)-(+)-malic acid, L-pyroglutamic acid , (S)-(+)-or (R)-( ⁇ )-1,1′-binaphthyl-2,2′-diyl, (+)-dibenzoyl-D-tartaric acid or ( ⁇ )-dibenzoyl-L- Examples include tartaric acid.
  • the compound of formula (I) having a hydroxy group can be synthesized by protecting and deprotecting the hydroxy group according to a conventional method.
  • the compound of the formula (I) can be obtained in the form of a free base or an acid addition salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds. On the other hand, the compound of formula (I) can be converted to an acid addition salt by treating with various acids according to a conventional method.
  • the compound of the present invention has an excellent antiallergic action as a non-steroidal drug, so that it can be expected to be used as a safe antiallergic agent with few side effects on humans and mammals.
  • the compounds of the present invention can prevent allergic diseases such as allergic dermatitis, allergic rhinitis, bronchial asthma, atopic dermatitis, contact dermatitis, hives, eczema, allergic ophthalmitis, hay fever. And / or useful as a therapeutic agent.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and its daily dose varies depending on the type of compound, administration method, patient symptom / age, etc.
  • oral administration usually about 0.01 to 100 mg, more preferably about 0.1 to 10 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 1 ⁇ g to 10 mg, more preferably about 10 ⁇ g to 1 mg per kg body weight of a human or mammal can be administered.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above.
  • a pharmaceutical carrier a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • citric acid glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized magnesium, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, Carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, stearic acid Magnesium, talc, tragacanth, bentonite, veegum, karuboki Vinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid
  • Examples of the dosage form of the preparation include tablets, capsules, granules, powders, solutions, syrups, suspensions, injections, suppositories, eye drops, ointments, coating agents, patches, inhalants and the like. . These preparations can be prepared according to a conventional method. In addition, these formulations may contain other therapeutically valuable ingredients.
  • Me means a methyl group
  • Ph means a phenyl group
  • i-Pr means an isopropyl group.
  • Abbreviations used for 1 H-NMR include: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple double line, q is a quadruple line, m is a multiple line, br is wide, brs is a wide single line, brd is a wide double line, brt is a wide triple line, and J is a coupling constant.
  • Step 1 Acetic acid (24.2 ml) was added to a solution of 1-t-butyloxycarbonylpiperidin-4-one (50.0 g) and aniline (19.5 g) in dichloromethane (250 ml), and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, sodium triacetoxyborohydride (40.9 g) was added to the reaction mixture, followed by stirring at room temperature for 12 hours. A saturated aqueous ammonium chloride solution (100 ml) was added to the reaction mixture, and extraction was performed with chloroform (100 ml ⁇ 3 times). The organic layer was washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Step 2 To a solution of 4-phenylaminopiperidine-1-carboxylic acid t-butyl ester (15.0 g) and triethylamine (18.9 ml) obtained in Step 1 above in dichloromethane (200 ml) was added chloromethane under nitrogen substitution and ice cooling. Acetyl chloride (9.2 ml) was added dropwise. After completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for 12 hours. A saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the reaction mixture, and the mixture was extracted with chloroform (50 ml ⁇ 3 times).
  • Step 3 To the mixture of 4- [N- (2-chloroacetyl) -N-phenylamino] piperidine-1-carboxylic acid t-butyl ester and potassium carbonate (26.3 g) obtained in Step 2 above in acetonitrile (300 ml). Piperidine (16.1 ml) was added and stirred for 12 hours under reflux. Water (50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml ⁇ 3 times). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Reference Example 1 (2) 2- (morpholin-4-yl) -N-phenyl-N- (piperidin-4-yl) acetamide
  • Reference Example 1 (3) 3- (4-methylpiperazin-1-yl) -N-phenyl-N- (piperidin-4-yl) propionamide
  • TMA Trimellitic anhydride
  • test drug was dissolved in DMSO (dimethyl sulfoxide) to a final concentration of 2.5% by weight the previous day, and then prepared in a 0.5% by weight methylcellulose (MC) solution for use as a comparative control compound.
  • DMSO dimethyl sulfoxide
  • MC methylcellulose
  • Prednisolone a steroidal agent, was prepared at 1 mg / mL. Each was orally administered twice at 0.5 mL / animal 30 minutes before induction and 4 hours after induction.
  • the compound of the present invention represented by the above formula (I) has an inhibitory effect equivalent to or higher than that of a steroid agent on the skin inflammatory reaction of an atopic dermatitis model animal. It was. This suggests that the compound of the present invention has an excellent antiallergic action and further has an anti-inflammatory action.
  • the compound of the present invention has an excellent antiallergic action in an atopic dermatitis model, and as an antiallergic agent, for example, allergic dermatitis, allergic rhinitis, bronchial Desirably alone for the prevention and / or treatment of asthma, atopic dermatitis, contact dermatitis, urticaria, eczema, allergic ophthalmitis, hay fever, and other inflammatory diseases If necessary, it can be used in combination with existing drugs.
  • an antiallergic agent for example, allergic dermatitis, allergic rhinitis, bronchial Desirably alone for the prevention and / or treatment of asthma, atopic dermatitis, contact dermatitis, urticaria, eczema, allergic ophthalmitis, hay fever, and other inflammatory diseases If necessary, it can be used in combination with existing drugs.

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Abstract

Cette invention concerne un nouveau composé utilisé comme agent antiallergique, à savoir un nouveau dérivé de 1-aminocarbonyl-pipéridine de formule (I) ou son sel physiologiquement acceptable. (I) (Dans la formule, le cycle A représente un groupe azétidine-1-yle, un groupe pyrrolidine-1-yle, un groupe pipéridino, un groupe pipérazine-1-yle, un groupe morpholino ou analogue; R1 représente un groupe phényle éventuellement substitué, un groupe cycloalkyle en C3-8 éventuellement substitué ou analogue; R2 représente un groupe phényle éventuellement substitué ou analogue; R3 et R4 peuvent être identiques ou différents et chacun représente un atome d'hydrogène, un atome d'halogène, un groupe hydroxy, un groupe alkyle en C1-6 ou semblable; et m représente 1, 2 ou 3.)
PCT/JP2009/054093 2008-03-04 2009-03-04 Nouveau dérivé de 1-aminocarbonyl-pipéridine WO2009110519A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005508907A (ja) * 2001-09-14 2005-04-07 ノボ　ノルディスク　アクティーゼルスカブ ヒスタミンｈ３受容体に選択的に結合する置換されたピペリジン
JP2005179351A (ja) * 2003-11-28 2005-07-07 Tanabe Seiyaku Co Ltd 医薬組成物
WO2006064351A2 (fr) * 2004-12-16 2006-06-22 Pfizer Limited Nouveaux composes
JP2007532555A (ja) * 2004-04-07 2007-11-15 ミレニアム・ファーマシューティカルズ・インコーポレイテッド 炎症性疾患の処置のためのｐｇｄ２レセプターアンタゴニスト
WO2008029924A1 (fr) * 2006-09-08 2008-03-13 Dainippon Sumitomo Pharma Co., Ltd. Dérivé d'aminoalkylcarboxamide cyclique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005508907A (ja) * 2001-09-14 2005-04-07 ノボ　ノルディスク　アクティーゼルスカブ ヒスタミンｈ３受容体に選択的に結合する置換されたピペリジン
JP2005179351A (ja) * 2003-11-28 2005-07-07 Tanabe Seiyaku Co Ltd 医薬組成物
JP2007532555A (ja) * 2004-04-07 2007-11-15 ミレニアム・ファーマシューティカルズ・インコーポレイテッド 炎症性疾患の処置のためのｐｇｄ２レセプターアンタゴニスト
WO2006064351A2 (fr) * 2004-12-16 2006-06-22 Pfizer Limited Nouveaux composes
WO2008029924A1 (fr) * 2006-09-08 2008-03-13 Dainippon Sumitomo Pharma Co., Ltd. Dérivé d'aminoalkylcarboxamide cyclique

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